The kinetic disposition of morphine and its metabolites in rats is being investigated. Special emphasis will be placed on their long persistance in the body and particularly the brain following single doses and an episode of morphine addiction, kinetics of brain entry and removal, regional brain distribution which may correlate to opiate receptor distribution at low morphine concentrations, and irreversible binding to insoluble tissue material. Kinetics of metabolites, e.g. normorphine, will be studied similarly following administration of the metabolite under investigation. The effects on morphine kinetic of coadministration of morphine antagonists, e.g. naloxone, and inactive congeners, e.g. dextrophane, which block specific and non-specific binding in the brain, will be investigated. Stable isotope effects on receptor binding and rate of metabolism using in vitro and in vivo administration of pharmacologically less active N-trideuteromethyl morphine will serve to further characterize determinants of morphine kinetic disposition. Stable isotope effects on receptor binding and rate of metabolism using in vitro and in vivo administration of pharamacologically less active N-trideuteromethyl morphine will serve to further characterize determinants of morphine kinetic disposition. Stable isotope dilution-mass fragmentography is the primary analytical tool, since extreme sensitivity and specificity are required. Kinetic models are being constructed, which include pharmacokinetics and in vivo opiate binding. Such a model, if providing a unique and accurate solution is capable of predicting receptor occupancy following morphine administration, which might correlate with dependence and withdrawal and will provide important knowledge on the pharmacology of opiates.